Pavlovian Conditioning Paradigm Research Articles

Effects of 3,4-Methylenedioxymethamphetamine on Conditioned Fear Extinction and Retention in a Crossover Study in Healthy Subjects.

Background: 3,4-Methylenedioxymethamphetamine (MDMA) has shown initial promise as an adjunct in psychotherapy to treat posttraumatic stress disorder (PTSD). Its efficacy and safety have been demonstrated across phase I–III studies. However, the mechanism underlying the potential utility of MDMA to treat PTSD in humans has not yet been thoroughly investigated. Preliminary evidence suggests that MDMA may facilitate fear extinction recall, which may be through the release of oxytocin. To test this hypothesis, we examined the efficacy of acute MDMA treatment to enhance fear extinction learning and recall. Methods: We used a two-period, double-blind, randomized, placebo-controlled crossover design in 30 healthy male subjects who received a placebo and a single dose of MDMA (125 mg). Fear extinction was tested using two separate Pavlovian fear conditioning paradigms, one using skin conductance response (SCR), and the other fear-potentiated startle (FPS) to conditioned cues. MDMA treatment occurred after fear conditioning and 2 h before extinction learning. Extinction recall was tested 23 h after MDMA intake. Additional outcome measures included subjective effects, emotion recognition tasks, plasma levels of oxytocin, and pharmacokinetics. Results: Fear conditioning and extinction learning were successful in both fear extinction paradigms (generalized eta–squared [ges] for SCR: 0.08; FPS: 0.07). Compared to placebo treatment, MDMA treatment significantly reduced SCRs to the reinforced conditioned stimulus (CS+) during extinction learning (ges = 0.03) and recall (ges = 0.06). Intensity of the subjective effects of MDMA (good effect, trust, and openness) during extinction learning negatively correlated with the discrimination between CS+ and the safety stimulus (CS−) during recall. MDMA did not influence FPS to conditioned cues. Oxytocin concentration was increased fourfold on average by MDMA during acute effects but was not associated with fear extinction outcomes. Conclusions: MDMA treatment facilitated rapid fear extinction and retention of extinction as measured by SCR to fear cues, in line with animal studies of MDMA facilitation of extinction. However, this effect may be limited to certain forms of learned fear responses, as it was not observed in the extinction model using startle reactivity as the outcome. This study provides further evidence for the facilitation of extinction with MDMA treatment and suggests this may be a component of its efficacy when paired with psychotherapy. Clinical Trial registration: clinicaltrials.gov identifier: NCT03527316

Neural, physiological, and psychological markers of appetitive conditioning in anorexia nervosa: a study protocol

BackgroundAnorexia nervosa (AN) is a chronic and disabling psychiatric condition characterized by low hedonic drive towards food, and is thought to be inclusive of altered dimensions of reward processing. Whether there exists a fundamental aberrancy in the capacity to acquire and maintain de novo hedonic associations—a critical component of hedonic responding—has never been studied in AN.MethodsThis multi-modal study will employ a 2-day Pavlovian appetitive conditioning paradigm to interrogate the (1) acquisition, (2) extinction, (3) spontaneous recovery and (4) reinstatement of appetitive learning in adolescents and young adults with AN. Participants will be 30 currently ill, underweight individuals with AN; 30 weight-restored individuals with AN; and 30 age-matched healthy controls, all aged 12–22 years. All subjects will undergo clinical assessment, followed by the 2-day appetitive conditioning task during which fMRI, pupillometry, heart rate deceleration, and subjective ratings will be acquired.DiscussionThis study will be the first to interrogate appetitive conditioning in AN—a disorder characterized by altered hedonic responding to food. Results will help establish objective biomarkers of appetitive conditioning in AN and lay the groundwork for developing novel lines of treatment for AN and other psychiatric disorders involving diminished ability to experience pleasure and reward.Trial registration: Pending.Intended registry Clinicaltrials.gov.

"Generalized unsafety" as fear inhibition to safety signals in adults with and without childhood trauma.

The Generalized Unsafety Theory of Stress posits that low heart rate variability contributes to a perception of "generalized unsafety" (i.e., constantly perceiving oneself to be unsafe), independent of stressful events or stress-related symptomatology. We tested this claim by examining if resting heart rate variability, trait worry, posttraumatic stress symptoms, trauma history, and age of onset predicted fear inhibition, a measure of generalized unsafety. A Pavlovian discriminant conditioning paradigm was used to assess fear inhibition level by comparing eyeblink startle potentiation to a threat cue (presented with air blast) with startle potentiation to a safety signal (never presented with air blast). Survey and laboratory responses were collected from 42 adults who were 20 years old on average, 86% Women, and 76% White. Heart rate variability did not independently predict variation in fear inhibition, as hypothesized. Rather, higher levels of posttraumatic stress symptoms and greater cumulative interpersonal trauma predicted lower fear inhibition. Individuals reporting childhood trauma had higher trait worry, which predicted more severe posttraumatic stress symptoms. These findings highlight the role of attenuated inhibitory learning in stress-related symptomatology and developmentally disruptive trauma. Ability to distinguish threat from safety is a plausible biobehavioral mechanism by which adversity impacts development.

History-dependent dopamine release increases cAMP levels in most basal amygdala glutamatergic neurons to control learning.

Dopaminergic inputs to basal amygdala (BA) instruct learning of motivational salience. This learning depends on intracellular plasticity signals such as cyclic adenosine monophosphate (cAMP), which is regulated by activation of dopamine receptors. We examine the dynamics of dopamine release and downstream signaling during multiple salient events occurring within tens of seconds. We perform real-time tracking and manipulation of cAMP in BA neurons invitro and invivo. Optogenetically evoked release of dopamine drives proportional increases in cAMP in almost all BA glutamatergic neurons, suggesting widespread actions of dopamine across neurons preferring positive or negative valence. This cAMP response decreases across trials with short intertrial intervals owing to depression of dopamine release. No such depression is evident when photostimulating cAMP production directly. cAMP and protein kinase A responses to repeated appetitive or aversive stimuli also exhibit pronounced depression. Thus, history-dependent dynamics of dopamine and cAMP may regulate learning of temporally clustered, salient stimuli.

Adult age-related differences in appetitive and aversive associative learning.

This study investigated age differences in appetitive and aversive associative learning using a Pavlovian conditioning paradigm. Appetitive and aversive associative learning is the process by which an initially neutral cue is systematically paired with an aversive or appetitive outcome, eventually itself prompting aversive or appetitive responses. Mimicking the motivational shift from a primary gain orientation in young adulthood toward a stronger orientation toward loss prevention in old age, we expected older adults to learn associations between novel stimuli and losses more rapidly than associating neutral cues with gains (here: donations to charity). A pilot study (N = 214, 18-81 years) established the equivalence of monetary gains and losses for a charitable donation across adulthood. Based on these data, an experiment using an associative conditioning paradigm assessed the extent and temporal dynamics of appetitive and aversive learning across adulthood (N = 122, 19-80 years). Results suggest that younger adults form gain-related associations at a higher learning rate compared to losses. By contrast, with increasing age, adults more rapidly track the valence of conditioned stimuli with losses than gains. This differential learning pattern cannot be attributed to age-differences in arousal or expectancy. Results suggest that the negative valence of losses drives learning more efficiently in older age groups, while younger age groups are more sensitive to the positive valence of gains. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Spreading depolarization induced by amygdala micro-injury prevents disruption of fear memory extinction in rats

Spreading depolarization (SD), a self-propagating wave of near-complete breakdown of the transmembrane ion gradients with water influx, regularly occurs in traumatized human brain. Here, we investigated long-term neurobehavioral consequences of injury-triggered SDs. Recently, we revealed that SD is reliably triggered by micro-injury of the amygdala, a key brain structure involved in fear processing. Using the classical Pavlovian fear conditioning paradigm, we investigated effects of the post-retrieval amygdala micro-injury and associated SD on fear memory in rats. We found that neither SD nor micro-injury alone affect fear response 24 h later but profoundly change it in subsequent extinction phase. If bilateral injury of the amygdala did not induce SD, fear extinction was severely impaired, while conditioned fear in rats with the identical amygdala injury triggering SD was successfully extinguished similarly to naïve rats. Our study provides first experimental evidence for involvement of injury-induced SD in extinction of traumatic fear memory.

Lateral hypothalamic LEPR neurons drive appetitive but not consummatory behaviors.

SUMMARYAssigning behavioral roles to genetically defined neurons within the lateral hypothalamus (LH) is an ongoing challenge. We demonstrate that a subpopulation of LH GABAergic neurons expressing leptin receptors (LHLEPR) specifically drives appetitive behaviors in mice. Ablation of LH GABAergic neurons (LHVGAT) decreases weight gain and food intake, whereas LHLEPR ablation does not. Appetitive learning in a Pavlovian conditioning paradigm is delayed in LHVGAT-ablated mice but prevented entirely in LHLEPR-ablated mice. Both LHVGAT and LHLEPR neurons bidirectionally modulate reward-related behaviors, but only LHVGAT neurons affect feeding. In the Pavlovian paradigm, only LHLEPR activity discriminates between conditioned cues. Optogenetic activation or inhibition of either population in this task disrupts discrimination. However, manipulations of LHLEPR→VTA projections evoke divergent effects on responding. Unlike food-oriented learning, chemogenetic inhibition of LHLEPR neurons does not alter cocaine-conditioned place preference but attenuates cocaine sensitization. Thus, LHLEPR neurons may specifically regulate appetitive behaviors toward non-drug reinforcers.

Binary Semantic Classification Using Cortical Activation with Pavlovian-Conditioned Vestibular Responses in Healthy and Locked-In Individuals.

To develop a more reliable brain–computer interface (BCI) for patients in the completely locked-in state (CLIS), here we propose a Pavlovian conditioning paradigm using galvanic vestibular stimulation (GVS), which can induce a strong sensation of equilibrium distortion in individuals. We hypothesized that associating two different sensations caused by two-directional GVS with the thoughts of “yes” and “no” by individuals would enable us to emphasize the differences in brain activity associated with the thoughts of yes and no and hence help us better distinguish the two from electroencephalography (EEG). We tested this hypothesis with 11 healthy and 1 CLIS participant. Our results showed that, first, conditioning of GVS with the thoughts of yes and no is possible. And second, the classification of whether an individual is thinking “yes” or “no” is significantly improved after the conditioning, even in the absence of subsequent GVS stimulations. We observed average classification accuracy of 73.0% over 11 healthy individuals and 85.3% with the CLIS patient. These results suggest the establishment of GVS-based Pavlovian conditioning and its usability as a noninvasive BCI.

Peripheral cortisol administration blunts reward arousal but heightens anxiety-like arousal in marmosets

AimsExcess hypothalamic-pituitary-adrenal (HPA) axis activation is common in people with major depression and generalised anxiety disorder. We sought to determine whether higher circulating levels of the glucocorticoid cortisol are causally related to the expression of anhedonia-like and anxiety-like behaviours in marmosets.MethodFour marmosets (two male, two female) took part in the study. Cortisol and saline control injections were administered intramuscularly and salivary cortisol samples were taken before and after injections to determine if circulating cortisol levels changed from pre- to post-injection. To measure anhedonia-like behaviours, we trained marmosets on an appetitive Pavlovian conditioning paradigm, where animals learn to associate two anticipatory auditory cues (conditioned stimulus + or conditioned sitmulus -, CS+ or CS-) with the presence or absence of food reward (unconditioned stimulus + or unconditioned stimulus -, US+ or US-). Using cardiovascular telemetry probes and video cameras, we recorded animals' cardiovascular and behavioural arousal in freely moving conditions, comparing the injection of saline control versus 5mg/kg, 10mg/kg or 20mg/kg intramuscular cortisol. To measure anxiety-like behaviours, we used a human intruder (HI) paradigm, where marmosets are confronted with an unfamiliar human in their home cage. We recorded their behaviour on video cameras after saline control or 20mg/kg intramuscular cortisol. We used an exploratory-factor analysis (EFA) to determine how marmosets' behaviours towards the intruder loaded onto an 'anxiety-like' score. We then compared these scores under saline control versus cortisol conditions. Significance was set at p < 0.05.ResultUnlike saline control, we found that subcutaneous injections of 20 mg/kg cortisol successfully elevated peripheral cortisol concentrations to levels equivalent to peak circadian concentrations (p = 0.023). In the appetitive setting, 5 mg/kg, 10 mg/kg and 20 mg/kg cortisol injections blunted anticipatory (CS+ induced) increases in behavioural arousal (p = 0.004) but did not alter anticipatory cardiovascular arousal. Consummatory behavioural and cardiovascular arousal also remained intact. In the HI test, 20 mg/kg cortisol injections moderately increased anxiety towards the intruder as measured by an increase in marmosets' EFA-derived anxiety-like scores (p = 0.035).ConclusionIn marmosets, elevated peripheral cortisol levels are causally related to the behavioural features of blunted reward anticipation together with elevated anxiety-like behaviours characteristic of mood and anxiety disorders. Future work will characterise the neuroimaging changes induced by elevated peripheral cortisol levels and identify the regions of the prefrontal cortex contributing to HPA axis regulation and dysregulation.

Dysregulation of threat neurocircuitry during fear extinction: the role of anhedonia

Dimensional models of anxiety and depression highlight common and distinct symptom clusters that are thought to reflect disruptions in underlying functional processes. The current study investigated how functioning of threat neurocircuitry relates to symptom dimensions of anxiety and depression. Participants were aged 18–19 years (n = 229, 158 female) and were selected to ensure a range of scores on symptom measures. Symptom dimensions of “General Distress” (common to anxiety disorders and depression), “Fears” (more specific to anxiety disorders), and “Anhedonia-apprehension” (more specific to depression) were evaluated. Participants underwent functional magnetic resonance imaging during a Pavlovian fear conditioning paradigm. Multilevel modeling analyses estimated relationships between symptom dimensions and activation in threat neural circuitry. Exploratory whole brain analyses were also conducted. Threat-related neural activity was not associated with General Distress or Fears. Anhedonia-apprehension was associated with activation of bilateral amygdala, anterior insula and dACC during late extinction. We found no evidence to support an association between symptom dimensions of General Distress or Fears with threat circuitry activation in a large sample of young adults. We did, however, find that the symptom dimension of Anhedonia-apprehension was significantly associated with threat-related neural activation during fear extinction. This effect requires replication in future work but may reflect anhedonic impairments in learning when contingencies are altered, possibly linked to the rewarding relief of an unexpectedly absent threat.

Transfer of incentive salience from a first-order alcohol cue to a novel second-order alcohol cue among individuals at risk for alcohol use disorder: electrophysiological evidence.

In susceptible individuals, cues associated with drug use are theorized to take on incentive-motivational properties, including the ability to reinforce higher-order, drug-related associative learning. This study aimed to test this prediction among people varying in risk for alcohol use disorder. Repeated-measures experiment with a measured individual difference variable at a University psychology laboratory in Missouri, USA. One hundred and six young adults (96 contributed complete data) were pre-selected to represent the upper and lower quartiles of self-reported sensitivity to alcohol's acute effects. Participants completed a second-order Pavlovian conditioning paradigm in which an initially neutral visual cue (second-order conditional stimulus; CS2 ) predicted onset of an olfactory cue (first-order conditional stimulus; CS1 ). Olfactory cues were isolated from alcoholic beverages, sweets and non-comestible substances, each presumed to have a natural history of first-order conditioning. Event-related potential responses to the CS2 across its conditioning and extinction, and to the CS1 , provided neurophysiological indices of incentive salience (IS). The IS of the alcohol CS1 was higher among participants low in alcohol sensitivity (LS), relative to their higher-sensitivity (HS) peers. The IS of the CS2 paired with the alcohol CS1 increased across the CS2 conditioning phase among LS but not HS participants. Also, LS (but not HS) individuals also experienced increases in alcohol craving following alcohol CS1 exposure, and this change was correlated with increases in the IS of the CS2 paired with the alcohol CS1 . Alcoholic beverage odor, a proximal cue for alcohol consumption, appears to reinforce conditioning of neurophysiological responses to a novel cue among low alcohol sensitivity (LS) individuals but not high alcohol sensitivity individuals, providing the first evidence that the LS phenotype may be associated with differences in the conditioned reinforcing properties of alcohol-related cues. These findings support the idea that the LS phenotype may increase alcohol use disorder risk via susceptibility to incentive salience sensitization.

A Novel Pavlovian Fear Conditioning Paradigm to Study Freezing and Flight Behavior.

Fear- and anxiety-related behaviors significantly contribute to an organism's survival. However, exaggerated defensive responses to perceived threat are characteristic of various anxiety disorders, which are the most prevalent form of mental illness in the United States. Discovering the neurobiological mechanisms responsible for defensive behaviors will aid in the development of novel therapeutic interventions. Pavlovian fear conditioning is a widely used laboratory paradigm to study fear-related learning and memory. A major limitation of traditional Pavlovian fear conditioning paradigms is that freezing is the only defensive behavior monitored. We recently developed a modified Pavlovian fear conditioning paradigm that allows us to study both conditioned freezing and flight (also known as escape) behavior within individual subjects. This model employs higher intensity footshocks and a greater number of pairings between the conditioned stimulus and unconditioned stimulus. Additionally, this conditioned flight paradigm utilizes serial presentation of pure tone and white noise auditory stimuli as the conditioned stimulus. Following conditioning in this paradigm, mice exhibit freezing behavior in response to the tone stimulus, and flight responses during the white noise. This conditioning model can be applied to the study of rapid and flexible transitions between behavioral responses necessary for survival.

Engagement of the Lateral Habenula in the Association of a Conditioned Stimulus with the Absence of an Unconditioned Stimulus

Neurons in the lateral habenula (LHb) are activated by reward omission and inhibited by reward delivery-reward processing functions opposite those of midbrain dopaminergic neurons. To further explore this, we examined the role of the LHb in associating a conditioned stimulus (CS) with the absence of an unconditioned stimulus (US) in an appetitive Pavlovian-conditioning paradigm. Rats underwent training in which a CS (light) was either paired (100% CS–US contingency) or unpaired (0% CS–US contiguity and negative contingency) with an US (food). Rats in the paired group exhibited steady acquisition of conditioned food-cup behaviors, while rats in the unpaired group showed low levels of response throughout training. After training, c-Fos levels were measured in the LHb, substantia nigra pars compacta (SNc), and ventral tegmental area (VTA) of rats in all groups. c-Fos levels were higher in the SNc/VTA of the paired group and the LHb of the unpaired group compared with the group with graded excitatory conditioning due to 50% of the CSs paired with USs and a low rate of USs presented during the intertrial interval and control groups for non-associative factors. The number of c-Fos–positive signals in LHb neurons projecting to dopaminergic midbrain neurons was higher in the unpaired group than in the paired group. Excitotoxic LHb lesions did not affect the acquisition of conditioned behaviors in the association of a CS with the presence or absence of an US. Significant increases in the numbers of c-Fos–positive neurons in the unpaired group suggest that LHb neurons engage in the process that associates a CS with the absence of an US.

A cognitively demanding working-memory intervention enhances extinction

Improving extinction learning has the potential to optimize psychotherapy for persistent anxiety-related disorders. Recent findings show that extinction learning can be improved with a cognitively demanding eye-movement intervention. It is, however, unclear whether [1] any cognitively-demanding task can enhance extinction, or whether it is limited to eye movements, and [2] the effectiveness of such an intervention can be enhanced by increasing cognitive load. Participants (n = 102, n = 75 included in the final sample) completed a Pavlovian threat conditioning paradigm across two days. One group underwent standard extinction (Control), a second group underwent extinction paired with a 1-back working memory task (Low-Load), and a third group underwent extinction paired with a 2-back working memory task (High-Load). We found that the conditioned response during extinction was reduced for both the Low-Load and the High-Load groups compared to the Control group. This reduction persisted during recovery the following day when no working memory task was executed. Finally, we found that within the High-Load group, participants with lower accuracy scores on the 2-back task (i.e., for who the task was more difficult) had a stronger reduction in the conditioned response. We did not observe this relationship within the Low-Load group. Our findings suggest that cognitive load induced by a working memory intervention embedded during extinction reduces persistent threat responses.

Sex differences in behavioral responses during a conditioned flight paradigm

Females exhibit greater susceptibility to trauma- and stress-related disorders compared to males; therefore, it is imperative to study sex differences in the mode and magnitude of defensive responses in the face of threat. To test for sex differences in defensive behavior, we used a modified Pavlovian fear conditioning paradigm that elicits clear transitions between freezing and flight behaviors within individual subjects. Female mice subjected to this paradigm exhibited more freezing behavior compared to males, especially during the intertrial interval period. Female mice also exhibited more freezing in response to conditioned auditory stimuli in the last block of extinction training. Furthermore, there were sex differences in the expression of other adaptive behaviors during fear conditioning. Assaying rearing, grooming, and tail rattling behaviors during the conditioned flight paradigm yielded measurable differences across sessions and between males and females. Overall, these results provide insight into sex-dependent alterations in mouse behavior induced by fear conditioning.

Social exclusion influences conditioned fear acquisition and generalization: A mediating effect from the medial prefrontal cortex

Fear acquisition and generalization play key roles in promoting the survival of mammals and contribute to anxiety disorders. While previous research has provided much evidence for the repercussions of social exclusion on mental health, how social exclusion affects fear acquisition and generalization has received scant attention. In our study, participants were divided into two groups according to two Cyberball paradigm conditions (exclusion/inclusion). Both groups underwent a Pavlovian conditioning paradigm, functional near-infrared spectroscopy (fNIRS), and skin conductance response (SCR) assessments. We aimed to determine the effects of social exclusion on fear acquisition and generalization and whether modulation of the medial prefrontal cortex (mPFC) mediates this relationship. Our results showed that socially excluded participants featured significantly higher and lower shock risk scores to safety stimuli (conditioned stimulus, CS-) and threatening stimuli (CS+), respectively, than did socially included subjects during fear acquisition. The exclusion group had increased skin conductance responses (SCRs) to CS and exhibited heightened shock risk and increased SCRs to generalized stimuli compared with the inclusion group. The fNIRS results demonstrated that the CS ​+ ​evoked larger oxy-Hb changes in the mPFC in the inclusion group than in the exclusion group during fear acquisition. Furthermore, the oxy-Hb of left mPFC of CS ​+ ​mediated the effect on the association between social exclusion and perceived risk of CS+ in the fear acquisition. Our results indicate that social exclusion impairs fear acquisition and generalization via the mediation of the mPFC and that social exclusion increases susceptibility to anxiety disorders through bias processing of fear discrimination in fear acquisition and generalization. By studying the role of social relationship in fear acquisition and generalization, our research provides new insights into the pathological mechanisms of anxiety disorder.

MDMA and Pavlovian Fear Memory: Dose‐Effect Analysis

±3,4‐methylenedioxymethamphetamine (MDMA) is a recreational drug that is also being pursued as a therapeutic for PTSD and other mood and anxiety disorders. Despite strong evidence of its therapeutic potential, these pursuits are hindered by evidence that MDMA produces robust neurotoxicity and cognitive deficits at high doses. These findings, however, may not generalize to typical recreational or therapeutic use of low‐dose MDMA. To date, there is little research on the cognitive effects of low/moderate doses of MDMA (less than 3 mg/kg) – the doses that users typically take. In the present study, we examined the effects of MDMA on learning and memory across a range of doses using a Pavlovian fear conditioning paradigm. Hybrid C57BL/6Jx129S1/SvImJ mice were randomly assigned to groups by MDMA dose. Mice were trained on‐drug with a single tone‐shock pairing and then tested off‐drug one week later for long‐term context and tone fear memory. We assessed the effects of doses of 0.1 to 8 mg/kg MDMA relative to vehicle control on immediate memory and long‐term contextual and cued memory. With increasing interest in therapeutic uses of MDMA, this research will help determine if low doses are therapeutically viable in terms of adverse effects on learning and memory.Support or Funding InformationSource Research Foundation (Connection Award to M.M.P.)

Comparing ABA, AAB, and ABC Renewal of Appetitive Pavlovian Conditioned Responding in Alcohol- and Sucrose-Trained Male Rats.

Conditioned responding can be renewed by re-exposure to the conditioning context following extinction in a different context (ABA renewal) or by removal from the extinction context (AAB or ABC renewal). ABA renewal is robust in Pavlovian and operant conditioning paradigms. However, fewer studies have investigated AAB and ABC renewal of appetitive conditioning, and those that did predominantly used operant conditioning tasks. Renewal has theoretical relevance for extinction and for exposure-based treatments for substance use disorders that aim to extinguish reactivity to drug-predictive cues. We therefore investigated ABA, AAB, and ABC renewal of Pavlovian conditioned responding to cues that predicted either alcohol or sucrose. Male, Long-Evans rats (Charles River) were exposed to either 15% ethanol (Study 1: “alcohol”) or 10% sucrose (Study 2: “sucrose”) in their home cages. Next, they were trained to discriminate between two auditory stimuli (white noise and clicker; 10 s) in conditioning chambers equipped with distinct olfactory, visual, and tactile contextual stimuli (context A). One conditioned stimulus (CS+) was paired with fluid delivery (0.2 ml/CS+; 3.2 ml/session; alcohol or sucrose in separate experiments), and the second CS (CS−) was not. In all sessions (conditioning, extinction, and test), each CS was presented 16 times/session on a variable-time 67-s schedule, and entries into the fluid port were recorded. CS+ port entries were then extinguished by withholding fluid delivery either in context A or in a second, different context (context B). Next, we assessed ABA, AAB, and ABC renewal in the absence of fluid delivery. During extinction, CS+ port entries were initially elevated in context A relative to context B. ABA renewal of CS+ port entries occurred in both alcohol- and sucrose-trained rats. ABC renewal approached statistical significance when data from both experiments were combined. No AAB renewal was observed, and, in fact, alcohol-trained rats showed AAB suppression. These results corroborate the reliability of ABA renewal and suggest that ABC renewal is a modest effect that may require greater statistical power to detect. From a treatment perspective, the lack of AAB renewal suggests that exposure-based treatments for substance use disorders might benefit from implementation in real-world, drug-use contexts.

Beyond arousal: Prediction error related to aversive events promotes episodic memory formation.

Stimuli encoded shortly before an aversive event are typically well remembered. Traditionally, this emotional memory enhancement has been attributed to beneficial effects of physiological arousal on memory formation. Here, we proposed an additional mechanism and tested whether memory formation is driven by the unpredictable nature of aversive events (i.e., aversive prediction errors). In a combined Pavlovian fear conditioning and incidental memory paradigm, participants saw initially neutral pictures from 2 distinct categories, 1 of which was associated with a risk to receive an electric shock. During encoding, we measured both physiological arousal and explicit prediction errors to explain memory differences in a surprise recognition test that followed approximately 24 hr later. In a first experiment, we show that physiological arousal, expressed as outcome-related skin conductance responses, was associated with improved recognition memory, corroborating arousal-based models. Critically, unsigned binary prediction errors derived from explicit shock expectancy ratings in each trial were also linked to enhanced recognition and model fits showed that the impact of prediction errors on memory was dissociable from the impact of arousal. In a second experiment, we replicated and extended the findings of the first experiment by demonstrating that the memory-promoting effect of prediction errors remained even after controlling for arousal. The present data point to prediction error-related learning as a cognitive mechanism that contributes to the emotional enhancement of memory, above and beyond the well-established effects of arousal in emotional memory formation. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Contextual Fear Conditioning Alter Microglia Number and Morphology in the Rat Dorsal Hippocampus.

Contextual fear conditioning is a Pavlovian conditioning paradigm capable of rapidly creating fear memories to contexts, such as rooms or chambers. Contextual fear conditioning protocols have long been utilized to evaluate how fear memories are consolidated, maintained, expressed, recalled, and extinguished within the brain. These studies have identified the lateral portion of the amygdala and the dorsal portion of the hippocampus as essential for contextual fear memory consolidation. The current study was designed to evaluate how two different contextual fear memories alter amygdala and hippocampus microglia, brain derived neurotrophic factor (BDNF), and phosphorylated cyclic-AMP response element binding (pCREB). We find rats provided with standard contextual fear conditioning to have more microglia and more cells expressing BDNF in the dentate gyrus as compared to a context only control group. Additionally, standard contextual fear conditioning altered microglia morphology to become amoeboid in shape – a common response to central nervous system insult, such as traumatic brain injury, infection, ischemia, and more. The unpaired fear conditioning procedure (whereby non-reinforced and non-overlapping auditory tones were provided at random intervals during conditioning), despite producing equivalent levels of fear as the standard procedure, did not alter microglia, BDNF or pCREB number in any dorsal hippocampus or lateral amygdala brain regions. Despite this, the unpaired fear conditioning protocol produced some alterations in microglia morphology, but less compared to rats provided with standard contextual fear conditioning. Results from this study demonstrate that contextual fear conditioning is capable of producing large alterations to dentate gyrus plasticity and microglia, whereas unpaired fear conditioning only produces minor changes to microglia morphology. These data show, for the first time, that Pavlovian fear conditioning protocols can induce similar responses as trauma, infection or other insults within the central nervous system.